Bottom Line:
Genotype- and phenotype-level correlations have been found between the clinical symptoms of achondroplasia and achondroplasia-specific FGFR3 mutations.Using quantitative real-time PCR analysis, GRB10 was over-expressed, and, using enzyme-linked immunosorbent assays for IGF1 and IGF-binding protein-3 (IGFBP3), we found that IGF1 and IGFBP3 were low-expressed in this patient.We demonstrate that a combination of uncommon, rare and exceptional molecular defects related to the molecular bases of particular birth defects can be analyzed and diagnosed to potentially explain the observed variability in the combination of molecular defects.

Background: Achondroplasia is a well-defined and common bone dysplasia. Genotype- and phenotype-level correlations have been found between the clinical symptoms of achondroplasia and achondroplasia-specific FGFR3 mutations.

Result: A 2-year-old boy with clinical features consistent with achondroplasia and Silver-Russell syndrome-like symptoms was found to carry a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene at c.1138G > A (p.Gly380Arg) and a de novo 574 kb duplication at chromosome 7p12.1 that involved the entire growth-factor receptor bound protein 10 (GRB10) gene. Using quantitative real-time PCR analysis, GRB10 was over-expressed, and, using enzyme-linked immunosorbent assays for IGF1 and IGF-binding protein-3 (IGFBP3), we found that IGF1 and IGFBP3 were low-expressed in this patient.

Conclusions: We demonstrate that a combination of uncommon, rare and exceptional molecular defects related to the molecular bases of particular birth defects can be analyzed and diagnosed to potentially explain the observed variability in the combination of molecular defects.

Mentions:
Currently, only 6 SRS patients have been shown to carry GRB10 duplications. In 1999, Joyce et al. described a mother and daughter who were both diagnosed with SRS and who both carried a duplication at 7p12.1-p13, which includes GRB10 and IGFBP1. The mother carried a paternally derived duplication, and the daughter carried a maternally derived duplication [13]. The next year, Monk et al. reported a de novo maternal duplication of 7p11.2-p13 in a patient with SRS [17]. Subsequently, two more individuals (A.C. and H.C.) with SRS were reported to possess larger duplications at this same locus: A.C. carried a maternally derived duplication, but the parent of origin for H.C.’s duplication was not known [16]. Recently, Eggermann reported a boy who displayed heterogeneous growth patterns and carried a de novo paternally derived duplication at 7p12.2 [6]. A few additional cases have been reported to the Decipher and ISCA databases (Fig. 4a, Table 1). All of these reported duplications involved the GRB10 gene, which is regarded as the most promising candidate gene at this locus (Fig. 2). Because all of these duplications were large (except Decipher case 289205, which had a partial GRB10 gene duplication), it is possible that neighboring genes, particularly genes such as IGFBP1 and IGFBP3, could contribute to SRS, and the involvement of these genes has not been completely ruled out in these cases. As a result, the correlations between SRS genotypes and phenotypes that are associated with duplications of GRB10 remain incompletely understood.Table 1

Mentions:
Currently, only 6 SRS patients have been shown to carry GRB10 duplications. In 1999, Joyce et al. described a mother and daughter who were both diagnosed with SRS and who both carried a duplication at 7p12.1-p13, which includes GRB10 and IGFBP1. The mother carried a paternally derived duplication, and the daughter carried a maternally derived duplication [13]. The next year, Monk et al. reported a de novo maternal duplication of 7p11.2-p13 in a patient with SRS [17]. Subsequently, two more individuals (A.C. and H.C.) with SRS were reported to possess larger duplications at this same locus: A.C. carried a maternally derived duplication, but the parent of origin for H.C.’s duplication was not known [16]. Recently, Eggermann reported a boy who displayed heterogeneous growth patterns and carried a de novo paternally derived duplication at 7p12.2 [6]. A few additional cases have been reported to the Decipher and ISCA databases (Fig. 4a, Table 1). All of these reported duplications involved the GRB10 gene, which is regarded as the most promising candidate gene at this locus (Fig. 2). Because all of these duplications were large (except Decipher case 289205, which had a partial GRB10 gene duplication), it is possible that neighboring genes, particularly genes such as IGFBP1 and IGFBP3, could contribute to SRS, and the involvement of these genes has not been completely ruled out in these cases. As a result, the correlations between SRS genotypes and phenotypes that are associated with duplications of GRB10 remain incompletely understood.Table 1

Bottom Line:
Genotype- and phenotype-level correlations have been found between the clinical symptoms of achondroplasia and achondroplasia-specific FGFR3 mutations.Using quantitative real-time PCR analysis, GRB10 was over-expressed, and, using enzyme-linked immunosorbent assays for IGF1 and IGF-binding protein-3 (IGFBP3), we found that IGF1 and IGFBP3 were low-expressed in this patient.We demonstrate that a combination of uncommon, rare and exceptional molecular defects related to the molecular bases of particular birth defects can be analyzed and diagnosed to potentially explain the observed variability in the combination of molecular defects.

Background: Achondroplasia is a well-defined and common bone dysplasia. Genotype- and phenotype-level correlations have been found between the clinical symptoms of achondroplasia and achondroplasia-specific FGFR3 mutations.

Result: A 2-year-old boy with clinical features consistent with achondroplasia and Silver-Russell syndrome-like symptoms was found to carry a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene at c.1138G > A (p.Gly380Arg) and a de novo 574 kb duplication at chromosome 7p12.1 that involved the entire growth-factor receptor bound protein 10 (GRB10) gene. Using quantitative real-time PCR analysis, GRB10 was over-expressed, and, using enzyme-linked immunosorbent assays for IGF1 and IGF-binding protein-3 (IGFBP3), we found that IGF1 and IGFBP3 were low-expressed in this patient.

Conclusions: We demonstrate that a combination of uncommon, rare and exceptional molecular defects related to the molecular bases of particular birth defects can be analyzed and diagnosed to potentially explain the observed variability in the combination of molecular defects.